Inherited Predisposition To Cancer

Although most genetic alterations in tumor cells develop during the life-time of a patient, the predisposition to cancers can be inherited. Three different types of inheritance can be distinguished.

In some families cancers are very frequent and occur (essentially) in each generation. This is a general hallmark of autosomal-dominant inherited diseases with high penetrance. The families may be plagued by specific cancers, rarer ones such as retinoblastoma, or common cancers such as breast cancer, or by various types of cancer, such as in Li-Fraumeni-syndrome (Table 2.2). Typically, cancers manifest at a lower than average age of onset and also unusually often at multiple sites or bilaterally in paired organs, such as the eyes, kidney and breast. These are two further criteria pointing to inherited cancers. In some cases, cancer predisposition is associated with developmental defects, e.g. in the Gorlin and Cowden syndromes. This is a fourth, although not as strict criterion. The increased risk in cancer families with an autosomal-dominant mode of inheritance is caused by an inherited mutation in a single gene. The affected genes are usually tumor suppressor genes (^5) and more rarely oncogenes (^4). The inherited mutations are likely not sufficient to cause cancer, but they provide the first mutation of several that are required (^2.5).

In some families predisposition to cancer is inherited in a recessive mode. More often than in the dominantly inherited cases, cancer predisposition is found in the context of rare inherited syndromes (Table 2.3). So, the affected patients are initially afflicted by other symptoms and cancers appear later, but still at a relatively early age. Syndromes in this category include Xeroderma pigmentosum, Ataxia telengiectasia, Fanconi anemia, Nijmegen breakage-syndrome as well as the Bloom and Werner syndromes. These syndromes differ in the extent of the cancer risk and the predominant cancer types, but at least one type of cancer is substantially more prevalent than in the general population. In these syndromes, predisposition to cancer is evidently caused by mutations inactivating both copies of the same gene. The genes affected are usually involved in cell protection and DNA repair (^3.4). In general, the inherited defects in DNA repair favor genetic alterations in somatic cells that lead to cancer.

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